The present invention relates to a medical composition and use thereof for the manufacture of a topical barrier formulation, an UV-radiation absorbing formulation, or an antiviral, antifungal, or antiinflammatory formulation.
Since the first epidemiological data on allergic contact dermatitis reported in the thirties, nickel has been the most frequent allergen in women. The primary site for sensitization has changed, from suspenders to metal buttons in jeans to pierced ear lobes. Sensitization may also occur from occupational contact with objects like electrical assembly, cuff links, locksmith tools, dental equipment, scissors, knitting equipment, chemical reagents etc.
In the following, the focus is on the severe condition of hand eczema, but obviously, eczema on other sites like the stomach caused by nickel containing jeans buttons or on ear lobes caused by contact with earrings is a big problem.
The sources of primary sensitization resulting in hand eczema are either occupational or environmental. Occupations include platers, metal workers, cashiers, hairdressers or office workers. Environmental primary sensitization include housewives, environment and hobbies with nickel exposure. In patients already sensitized to nickel, the risk of acquiring hand eczema is far greater, especially when the skin is damaged. In many cases a multifactorial situation, including nickel exposure, exposure to irritants, atopic constitution and other factors plays a role. Investigations in the USA, Finland and Denmark have shown that the number of nickel sensitive women in the general population approximates 10% (1,2,3).
However, a higher frequency of nickel allergy (15-18%) is found in the age groups where hand eczema commonly develops (4). When hand dermatitis develops in the nickel sensitized subjects, the condition becomes a definite threat to the individual""s working ability. In a study from Denmark it was shown that nickel hand eczema is the most common skin disease which leads to permanent disability (5). This results in huge costs for the social welfare system and in personal suffering for the patients. In another Danish study (6) based on a questionnaire sent to a stratified sample (2500) of the female population, it was concluded that 43% of the nickel sensitive subjects reported hand eczema. The study also demonstrated that women who were nickel sensitive ran an increased risk of developing hand eczema compared to non-nickel-sensitive women. Also, those who already had a hand eczema were more likely to develop nickel allergy. As pointed out earlier, the risk of developing nickel allergy increases when the skin is injured as is the case in e.g. irritant contact dermatitis caused by exposure to irritants like detergents in working or home environment. A study investigating the bioavailability of nickel from consumer products was made (7) and the provocation threshold in nickel sensitive patients varied from 0.47 xcexcg to 5.2 mg.
The current method for treating nickel dermatitis is basically to treat the acute eczema with corticosteroid creams and advise the patients to avoid nickel containing objects, which is obviously a difficult task. Another method that has been used experimentally is to administer nickel chelating agents like disulfiram (8). Although some improvement of the patients"" eczema was achieved, side effects in the form of flare-up reactions and hepatotoxicity was noted. Triethylenetetramine has been used in the same manner, however without resulting in any significant improvement (9). In addition, reports of teratogenicity in rats by triethylenetetramine indicated a limited value of the method.
A recent review of the use of binding agents and barrier creams (10) showed that the most effective nickel chelating substance is 3% clioquinol applied topically in a cream in combination with 1% hydrocortisone. The method used was patch testing with cream-coated 20 pence coins in 26 nickel-sensitive subjects (11).
However, clioquinol toxicity has been found in dogs treated daily with 5 g of a 3% preparation for a month, and there may be a risk of toxicity in infants and children from its topical use. Also, clioquinol is a known contact allergen and is present in the European Standard Series for the detection of contact hypersensitivity. It is therefore considered unsuitable for the purpose of preventing nickel dermatitis. A certain effect, expressed as decreased patch test reactivity, was found for EDTA in combination with 1% hydrocortisone, where only 40% of the subjects showed reduced nickel patch test reactivity (11). The purpose of using an active barrier cream is to prevent nickel from coming into contact with the epidermis of the skin, and to avoid use of corticosteroid topical treatment on the inflammation of the skin. The negative effects of prolonged use of corticosteroids is well known.
In another study (12), where pretreatment of a cream containing 10% Na2H2EDTA was used, somewhat better results were achieved in reducing patch test reactivity (76%). The maximum challenge concentration in this study was however only 1% of nickel sulfate, compared to 5% which is normally used in patch testing. A patch test study (13) in 21 nickel sensitive individuals where nickel discs were applied on top of Carbopol barrier gels containing 10% CaNa2EDTA showed that the discs without pretreatment gave a positive reaction in 11 out of the 21 subjects. All of the subjects showed a positive reaction to 5% nickel sulfate. Since only 11 out of 21 subjects reacted to the discs, it seems that the release of nickel ions from the discs was insufficient for inducing a positive reaction. The 11 subjects positive to the challenge by the disc did not react when the disc was applied on top of the barrier gel. A blank gel without CaNa2EDTA also showed a reduction in sensitivity where 3 out of 11 showed a positive reaction on challenge to the disc and 7 patients showed a reduced reaction when treated with the vehicle.
From an experiment in vitro it was shown that the gels caused an increase in the release of nickel ions from the alloys. This is considered as an unwanted effect since it counteracts the barrier effect of the formulation.
Studies using tin complexes with EDTA, cyclohexane-1,2-diaminetetraacetic acid (CDTA) and diethylenetri-aminepentaacetic acid showed only poor results in chelating nickel, chromium and cobalt (14). The fact that none of the above mentioned creams have resulted in any commercially used product further underlines the need for developing an effective active nickel barrier cream.
Cobalt allergy is often associated with nickel allergy because the metals are often associated with each other. A positive test to cobalt occurs 20 times more frequently in those allergic to nickel than in those not allergic. The frequency of cobalt patch test positive patients is around 7%, and of-these around 50% are isolated reactions. However cobalt also occurs isolated in various products such as printing inks, paints, polyester resins, electroplating, wet alkaline clay in pottery, porcelain dyes, animal feeds.
Trivalent chromium penetrates the skin very poorly, binding to proteins on the surface of the skin, whereas hexavalent chromium penetrates the skin easily but binds poorly to proteins on the surface of the skin. It is thought that hexavalent chromium penetrates the epidermis and is then reduced by enzymes to the trivalent form which combines with proteins to form the allergenic compound.
The true frequency of patch test positive patients to chromate is probably in the range of 2-4%. The most common cause of chromate allergy is contact with cement. Other sources are from chrome-tanned leather, antirust paint, timber preservatives, matches with chromate in the match head, coolants and machine oil and many other sources.
Dermatitis from chromate sensitivity is normally quite severe and has a poor prognosis.
Allergic reactions on the skin and oral mucosa induced by gold, i.e. the Au+ and Au3+ ions, have also been encountered and is a problem for several persons, especially in dental treatment.
Oral hyposensitization in nickel allergy with repeated oral doses of nickel sulfate has been studied (15). The degree of contact sensitivity was found to decrease especially when higher doses of nickel sulfate was administered (5 mg/week). However, the majority of patients had a flare-up of their dermatitis and it was concluded that high oral doses are inconvenient to the patients. Other models have been evaluated against Rhus allergens where a moderate decrease in Rhus sensitivity was found after oral or intramuscular administration of Rhus allergens (16). Another hyposensitization study was made on North American healthy subjects sensitized to the poison ivy and poison oak allergen urushiol (17). Increasing oral doses of urushiol were given over a protracted period and resulted in a lowered degree of patch test reactivity. Side effects in the form of rashes and anal pruritus were the main complications.
From the above discussion it is evident that there is no current effective treatment or product that does not cause undesired side effects, that can be used effectively for the prevention of nickel or related metal dermatitis or dermatitis caused by organic allergens found in materials such as Rhus or Poison ivy or Poison oak. The latter allergen containing plants cause wide-spread dermatitis in many subjects in especially North America.
This underlines the importance of developing products that actively can facilitate the prevention of contact dermatitis from metals or organic allergens either through an active barrier function via strong chelating properties or by induction of tolerance in sensitized individuals. Further, there is an urgent need for a barrier formulation that protects from irritation caused by various agents such as detergents, alkaline and acidic products and solvents, combined with an active metal-chelating agent that prevents from metal sensitization. This is due to the fact that irritant dermatitis often coexists with allergic contact dermatitis caused by metals, and that these two conditions aggravate the symptoms of the patients. A model of testing the efficacy of general barrier creams (without addition of any active chelating agent) against irritants has been developed (18). Sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), lactic acid and toluene were used as irritants. Partial protection was shown for two commercial creams to SLS, NaOH and lactic acid, but not to toluene. Generally, xe2x80x9cnon-activexe2x80x9d barrier creams against irritation might in fact enhance the penetration of allergens such as nickel through the epidermis, although some are marketed as being effective also in the protection against allergens. This fact further emphasizes the importance of a combined formulation including an active chelating agent in a barrier cream against irritants.
Further, currently skin diseases such as photoaging, skin cancer, sunburn, drug phototoxicity, hyperpigmentation, UV-induced immunosuppression and diseases aggravated by sunlight are treated by means of protecting the skin against UV A and UV B radiation. Protecting agents are various UV A and UV B absorbing sunscreens such as benzophenones, dibenzoylmethane, methylanthranilate, Padimate-O or physical sunscreens such as zinc oxide or titanium oxide. Also, tretionin, pigment inducing agents (5-MOP), antioxidants and free radical scavengers are used. These protective agents however give an inadequate protection and several agents are also contact and photo-contact sensitizers. An effective UV A and UV B protecting topical formulation with low toxicity and allergenicity would be a valuable addition to the present agents in the protection against diseases induced by UV A and UV B radiation.
There is also a constant strive in the development and need for better and less toxic antivirus agents for the therapy of viral infections. A major advance was the development of Acyclovir that exerts selectivity in the inhibition of virus replication at low concentrations. Although this agent is used in various dosages and delivery routes against Herpes simplex viruses 1 and 2 and varicella zoster virus it has its limitations due to poor absorbtion from the gastrointestinal tract, weak action against varicella zoster virus and is inactive against cytomegalo virus as well as showing drug resistance pattern. An active topical formulation with low toxicity and allergenicity would be a valuable addition to the present agents in the treatment of viral infections.
Further, imidazol derivatives such as ketoconazole, econazole, miconazole and clotrimazole as well as terbinafine are currently used as topical treatment against fungal diseases induced by dermatophytes and pityriasis versicolor causing skin and nail infections as well as candida also causing infection on the mucosa. More severe infections are treated with oral agents such as griseofulvin, ketoconazole, terbinafine, itraconazole and fluconazole. Undesired effects in the form of hepatotoxicity, altered liver function, gastrointestinal side effects and skin reactions have been noted for the oral agents and contact allergic reactions for the imidazol derivatives have been showed. An active topical formulation with low toxicity and allergenicity would be a valuable addition to the present agents in the treatment of fungal infections.
Some prior art formulations contain chitosan or chitosan derivatives in combination with dietylene triamine penta acetic acid (DTPA).
Nihon Mediphysics has, in JP 08-0112579, proposed the use of topical agents for radiotherapy of cancer. The formulation is based on a hydrophilic gel forming polymer, e.g. chitosan, covalently bound to a radioactive metal ion via a complexing agent. The-radioactive metal ion is specified to be the indium (III) isotope. This patent application is clear-cut limited to the topical treatment of cancer in combination with radiation therapy. In contrast, the products according to the present invention are not intended for use in medical radiotherapeutic treatments. The purpose is inter alia protection against development of contact dermatitis, or pharmaceutical treatment thereof. Further, in one embodiment of the present invention the formulation is based on a soluble anionic metal chelating agent, e.g. DTPA, and not on DTPA covalently bound to the polymer. The anionic DTPA interacts with a cationic hydrophilic polymer, e.g. chitosan, and not with uncharged derivatives thereof.
Catalysts and Chemical Ind Co has in another Japanese patent specification, JP 07-112128, proposed the use of adsorption agents for the separation of nickel, cobalt, and aluminum from chemical engineering or chemical processes. This publication also refers to a covalent derivative of chitosan in reaction with either ethylenediaminetetraacetic acid (EDTA) or DTPA. This application is neither intended for, nor applicable for medical use of any kind, only for the separation of metal ions in chemical processes.
Antioxidant skin cosmetics containing ascorbyl esters, thiols and completing agents, e.g. DTPA, have been proposed in FR 2 610 626 to protect especially skin lipids from oxidation. The purpose of that invention is the protection against chemical interaction with oxygen and oxygen species, where the complex forming agents stabilize e.g. endogenous ferric ions from participation in the oxidative skin reactions, and are certainly not intended to chelate exogenous allergenic metal ions.
In WO 92/09636, a method is proposed for protecting the skin and minimizing skin irritation by the topical use of protective compositions. This publication deals with a physical barrier formulation, composed of compounds with film-forming protective properties. The composition is intended to protect the skin from contact with irritant allergenic or toxic agents. However, the formulation is deficient in active protection of low or high molecular weight compounds. The protection is intended to be achieved only by the use of derivatives of chitosan, or in combination with anionic polymers, but not by native chitosan. The combination of the different types of polymers is supposed to optimize the film-forming properties of the composition. However, in clinical studies in humans with contact dermatitis caused by poison oak/ivy, the protective effect exerted by the compositions tested were not significant. The results indicate that the barrier effect based on physical mechanisms is insufficient, i.e. the allergenic compounds can still be transferred across the skin barrier and provoke the allergic inflammatory reaction.
The inhibitory effect of various topical chelating agents on nickel-contact dermatitis has been reviewed recently (Cont. Derm. 32: 257-265: 1995) and studied previously after treatment with barrier ointments containing EDTA (J. Am. Acad. Dermatol. 30: 560-565: 1994; Cont. Derm. 26: 197. 1992. and Cont. Derm. 11: 311-314: 1984). The results from clinical studies indicate that EDTA significantly blocks the allergenic effects of nickel in some nickel sensitive patients. However, this complexing agent is not sufficiently effective in all patients. The chelating effect of tin complexes with e.g. DTPA has also been studied, and the compounds were found ineffective as nickel chelators. The unique combination of DTPA or analogous metal ion complexing agents with cationic, hydrophilic amino-containing polymers, which constitutes an accomplished effective active nickel barrier formulation, has not been described previously.
The object of the invention is to eliminate or alleviate the above-mentioned problems associated with different dermatological skin and mucosa related disorders induced by allergens, skin irritating agents, ultraviolet radiation, viruses, fungi, and inflammatory inducing factors.
This object is achieved according to the present invention with a medical composition which is defined in the characterising part of the independent claims. Preferred embodiments of the present invention are also defined in the dependent claims.